Aging encompasses problems, especially psychological, behavioral, systemic, and sexual dysfunction. The process of aging not only involves disabilities and health related morbidities but also a wide array of psychological aspects. The process in men involves modifications in testosterone levels, with psycho-physical outcomes of variable intensity.
The main action of the steroid hormone testosterone is the intensifying of the primary and secondary sex characteristicts of human males, as well as the maintaining of the functions associated therewith. Apart from this main effect testosterone has a number of secondary effects, which are of great importance for the stressability and performance characteristics of the human organism. These include the maintaining of an anabolic metabolic situation, the restoration of the performance of human males following exhausting exercise, and increasing the psychophysiological stressability and stress resistance.
The action mechanisms of testosterone have been investigated in detail. The secondary effects on the psychophysiological state have, according to research, been attributed to the presence of testosterone receptors in the central nervous system.
Over 90% of the testosterone in the blood is bound to protein, and the biologically active component is free testosterone, representing 4% to 8% of the total concentration in the blood. The testosterone concentration in the blood is subject to a physiologically daily cycle (maximum concentration in the morning), a seasonal cycle (lowest concentration in May), and influences by living circumstances and aging processes.
The overall testosterone concentration in the blood is individually very stable under normal conditions. Intense physical effort, long-lasting stressful situations, and unfavorable diet lower the blood level of testosterone. With increasing age, and in particular, from about the age of thirty in human males, there is a reduction of the free testosterone concentration. It has been established that testosterone decreases by approximately 1% per year after age thirty (30).
In human males, small amounts of estrogen are produced by aromatization of testosterone both in the testes and peripheral tissues. Although present in only small amounts, generally less than one-fourth to one-tenth of that in premenopausal women, estrogen may play a role in the regulation of the male hypothalamic pituitary gonad axis, bone development, development of the prostate, and metabolic function. In the hypothalamus, conversion of testosterone to estrogen results in negative feedback on gonadotropin release. Estrogens thus normally reduce circulating testosterone and anti-estrogens result in corresponding increases. As men age, the proportion of fat to lean tissue gradually increases. Aromatization of testosterone in fat may lead to gradually increased estrogen-to-testosterone ratios and negative feedback that reduces total testosterone levels.
These changes lead to a reduced general performance, to higher time requirements for restoring the organism after exhaustive exercise, and to a reduction of the psychophysiological stressability and stress resistance. Research on physically and cyclically highly stressed persons has revealed that a rise in the testosterone level in the upper part of the individual physiological fluctuation range leads to a cancelling out of this negative situation, and to an increase in the general performance characteristics. The increase in the testosterone level in human males has consequently become part of preventative and therapeutic concepts in medical treatment of aging males.
There are several pharmaceutical methods to restore testosterone levels in humans with suboptimal levels. Many of these have disadvantages however. Testosterone esters in oil depot form have been used as injections for decades, however these injections can be inconvenient and often painful. These depot injections also result in inconsistent blood levels as a supraphysiological surge is seen soon after injection, but by the time the next injection is due, the levels often have dropped down below standard physiological levels. This is in contrast with testosterone levels under normal conditions, which are quite stable within mild release pulses of approximately 90 minute duration. Supraphysiological surges that are seen with injectable preparations may increase the incidence of undesirable side effects (i.e. prostate hypertrophy) as well as cause an amplified shutdown of the hypothalamic/pituitary testicular axis (“HPTA”).
Other pharmaceutical methods of androgen replacement therapy include synthetic oral androgen derivatives. These compounds (i.e. methyltestosterone and fluoxymesterone) are altered in the 17 alpha position of the steroid molecule with an alkyl group. This alkyl group renders the steroid impervious to oxidation of the 17 beta hydroxyl group in the liver and therefore greatly improves its oral bioavailability compared to the non-alkylated steroids. However, this structural modification also has been associated with a greatly increased risk of hepatotoxicity. Therefore, these synthetic compounds are far from an ideal solution.
Hypogonadism is recognized as a common occurrence in older males. A number of studies have suggested that hypogonadism may result in some of the observed decrements in muscle and skeletal mass associated with advancing age. The prevalence of hypogonadism in men is approximately 20% in men in their seventh decade with biochemical evidence of androgen deficiency, which increases to 50% of men in the eighth decade of life.
According to Indian Census 2011, India has the largest number of people with ages above sixty (60) years and these account for 9% of India's total population. By the year 2050, the number of elderly people in India will grow to 25% of the population, i.e., from 62 million to 240 million (Government of India: “Population Totals” Census; 2011. Accessed: 10 Sep. 2013).
By the year 2030, 20% of the U.S. population will be sixty-five (65) years of age or older, a figure that will include more than 20 million men. Significantly, the fastest growing segment of the older adult population is the oldest age group: those older than 85 years of age. Current estimates indicate that the number of individuals eighty (80) years of age or older in the United States will rise from 9.3 million in 2000 to 19.5 million in 2030, an increase of more than 100% (J. Kellogg Parsons, Curr. Bladder Dysfunct. Rep. (2010) 5:212-218).
Andropause or “male climacteric” is defined herein as a clinical and biochemical syndrome associated with aging and characterized by a set of typical symptoms, as well as testosterone deficiency.
The symptoms include alterations in the sexual, physical, and mental domains. The sexually related manifestations include reduced libido, erectile dysfunction, and decreased ejaculatory force and volume. The condition also results in easy fatigability, lethargy, hot flushes, blushing and sweating, depression, mood swings, nervousness, anxiety and irritability, poor concentration/memory, adiposity, reduction in strength, and bone/joint complaints. Testosterone deficiency has been associated with hip fracture and bone mass has been correlated with testosterone levels in older persons.
Although measurement of free testosterone is the gold standard for diagnosis of primary and secondary hypogonadism, due to financial and technical constraints it may not be possible to measure free testosterone levels in all of the situations. Therefore, attempts were made to develop certain noninvasive or non-interventional tools to diagnose hypogonadism on the basis of clinical presentation. These tools were developed to screen men who exhibited these general symptoms for a suite of other possible deficiencies, so that the chance of making the correct clinical diagnosis could be improved.
Morales et al. have described andropoause as a misnomer, and suggested a new term, Androgen Deficiency of the Aging Male (“ADAM”), a questionnaire that has a sensitivity of 88% and a specificity of 60% in men (Morales et al., 10(2) AGING MALE 57-65 (2007)), while some others preferred the term Partial Androgen Decline in Aging Males (“PADAM”) or Aging-Associated Androgen Deficiency (“AAAD”) (Matsumoto, Andropause: Clinical implications of the decline in serum testosterone levels with aging men, 57A J. GERONTOLOGY: MED. SCIS. M76-99 (2002); Morales et al., Andropause: A misnomer for a true clinical entity, 163 J. UROLOGY 705-12 (2000)). The most widely used tools including Aging Males' Symptoms (“AMS”) scale and the Derogatis Interview for Sexual Functioning (“DISF”).
The AMS scale is a health-related quality of life scale (“HRQoL”) and was originally developed in Germany in 1999 (Heinemann et al., A New ‘Aging Male's Symptoms’ (AMS) Rating Scale, 2 AGING MALE 105-14 (1999)). The scale was designed as a self-administered scale: (a) to assess symptoms of aging (independent of those that are disease-related) between groups of males under different conditions; (b) to evaluate the severity of symptoms over time; and (c) to measure changes pre- and post-androgen therapy. The AMS scale was developed in response to the lack of fully standardized scales to measure the severity of aging symptoms and their impact on HRQoL in males, specifically. See Daig et al., The Aging Males' Symptoms (AMS) scale: review of its methodological characteristics, 1 HEALTH & QUALITY OF LIFE OUTCOMES 77 (2003), and references cited therein.
The DISF is a coordinated set of brief-matched instruments designed to provide an estimate of the quality of an individual's current sexual functioning. It comprises twenty-five (25) questionnaire items and reflects quality of sexual functioning in the multi-domain format. All of the instruments in the DISF series are designed to be interpreted at three distinct levels: discrete items, functional domains, and aggregate summary (total) score. The DISF items are arranged into five primary domains of sexual functioning: sexual cognition/fantasy, sexual arousal, sexual behavior/experience, orgasm, and sexual drive/relationship. In addition, an aggregate DISF total score is computed that summarizes quality of sexual functioning across the five primary DISF domains. See MALE SEXUAL DYSFUNCTION: PATHOPHYSIOLOGY & TREATMENT 255 (Fouad R. Kandeel ed., Informa Healthcare 2007).
First, on a wide variety of measures, men show greater sexual desire than do women. Second, compared with men, women place greater emphasis on committed relationships as a context for sexuality. Third, aggression is more strongly linked to sexuality for men than for women. Fourth, women's sexuality tends to be more malleable and capable of change over time. Letitia Anne Peplau, 12 AM. PSYCHOLOGICAL SOC'Y: CURR. DIRECTIONS IN PSYCHOLOGICAL SCI. 37-40 (2003).
Stated broadly, women are more strongly affected by estrogen and progesterone, males by testosterone. These hormones are contrasting in their effects. Progesterone, for instance, is a female growth hormone and also the bonding hormone. Testosterone is the male growth hormone and also the sex-drive and aggression hormone. Hence it is not likely that the drugs effective for female libido would show efficacy for male libido as well.
Fenugreek (Trigonella foenum-graecum) has attracted considerable interest as a natural source of soluble dietary fiber and diosgenin (sapogenins). The fenugreek seed constains a central hard, yellow embryo surrounded by a corneous and comparatively large layer of white, semi-transparent endosperm. This endosperm contains galactomannan gum. The endosperm is surrounded by a tenacious, dark brown husk. The color of the gum fraction depends on the amount of outer husk (brown color) and cotyledon (yellow color) present.
There are commercial uses for the various fractions of the fenugreek seed. The commercial fenugreek oleoresins are used as an ingredient for imitation maple flavors and are effective in butter, butterscotch, black walnut, nut, and spice flavors. Another fraction of the fenugreek seed has been found to be a quantity of saponins. Fenugreek seed saponins, including sapogenins, are steroidal in nature, with diosgenin as the main sapogenin Disogenin is used by the drug industry as a precursor to progesterone (steroid hormones), which is used in the manufacturing of oral contraceptives.
U.S. Pat. No. 5,997,877 to Chang, and references cited therein, discloses a process for the recovery of substantially pure extracts from fenugreek seed, said process comprising mixing the fenugreek seed with a solvent for a period of contact time at a certain temperature such that certain seed components of the fenugreek seed are absorbed by the solvent; separating extracted fenugreek seed from the solvent, which solvent now contains extracted seed components; and separating the extracted seed components from the solvent, to yield seed components and spent solvent.
WO 2014/089344A2 to Bhaskaran et al., and references cited therein, discloses a method of enhancing female sexual drive and libido by administering a fenugreek extract but it does not provide any motivation to use the fenugreek extract in male libido.
Therefore, if a use of fenugreek, fenugreek seeds, or extracts thereof, to enhance psychological, somatic, and sexual conditions in an aging male human subject could be found, this would represent a useful contribution to the art. Further, if a use of fenugreek, or extracts thereof, to reduce symptom severity, improve sexual functioning, prevent further decline of sexual hormones, and/or improve sexual hormonal level in an aging male human subject could be found, this would represent a useful contribution to the art.